Low-density lipoprotein receptor-related protein-associated protein (LRPAP1) gene IVS5 insertion/deletion polymorphism is not a risk factor for gallstone disease in a Polish population

BACKGROUND: There is growing evidence that gallstone formation may be genetically determined. It was recently presented that a common polymorphism in the LRPAP1 gene might be associated with gallstone disease. AIM: Since reproducibility of data is important in genetic association studies, a case control study was designed to find out whether LRPAP1 gene polymorphism is associated with gallstone disease in a Polish population. SUBJECTS: Two hundred eighty-nine Polish Caucasian gallstone disease patients and 251 healthy controls participated in the study. METHODS: A 37-bp insertion/deletion polymorphism in intron 5 of LRPAP1 (rs11267919) was determined by means of polymerase chain reaction assay. RESULTS: The frequencies and distribution of the insertion/deletion alleles did not differ significantly between gallstone disease patients and controls. No significant gender-related differences in allele frequencies or distributions were noted. CONCLUSION: The LRPAP1 insertion/deletion polymorphism is not associated with gallstone disease in a Polish population.     

Association of APOE-C1 gene cluster polymorphisms with gallstone disease

BACKGROUND: Genetic polymorphisms in apolipoprotein genes may be associated with alteration in lipid profile and susceptibility to gallstone disease. AIM: To find out the association of APOE HhaI and APOC1 HpaI polymorphisms with gallstone disease. SUBJECTS: HhaI polymorphism of APOE and HpaI polymorphism of APOC1 were analysed in DNA samples of 214 gallstone patients and 322 age- and sex-matched healthy controls. METHODS: For genotyping DNA samples of all study subjects were amplified using polymerase chain reaction, followed by restriction digestion. All statistical analyses were done using SPSS v11.5 and ARLEQUIN v2.0 softwares. RESULT: APOC1 HpaI polymorphism was found to be significantly associated with gallstone disease. Frequency of H2H2 was significantly higher (P = 0.017) in patients than in controls and it was imposing very high risk (OR 9.416, 95% CI 1.125-78.786) for gallstone disease. When data were stratified in male and female, H2H2 was associated (P = 0.011) with disease in females only. Analysis at allele level revealed no association. APOE HhaI polymorphism and APOE-C1 haplotypes showed no association with gallstone disease. CONCLUSION: APOC1 HpaI polymorphism is associated with gallstone disease and shows gender-specific differences. APOE HhaI polymorphism may not be associated with gallstone disease.     

Association of low density lipoprotein receptor related protein-associated protein (LRPAP1) gene insertion/deletion polymorphism with gallstone disease

BACKGROUND AND AIM: Gallstones are byproducts of cholesterol supersaturated bile. Various studies have indicated that there might be a genetic predisposition to the disease. Receptor-associated protein (RAP) is a molecular chaperone for low density lipoprotein receptor-related protein (LRP), which plays a key role in cholesterol metabolism. Intron 5 insertion/deletion polymorphism of RAP gene (LRPAP1) has been implicated in other diseases sharing etiology with gallstone disease (GSD). METHODS: To analyze the association of insertion/deletion polymorphism in GSD, 130 gallstone patients and 202 healthy subjects took part in the present study. For genotyping, polymerase chain reaction was followed by 2% agarose gel electrophoresis. RESULTS: The results showed that frequencies of D and I allele were 65.77% and 34.23% in patients, 76.24% and 23.76% in controls, respectively. Frequency of I allele was significantly higher in the patient group than in the control group (P = 0.003). CONCLUSION: In the present study I (insertion) allele was found to be associated with GSD.     

Angiotensin-converting enzyme gene I/D polymorphism increases the susceptibility to hypertension and additive diseases: A study on North Indian patients

Angiotensin-converting enzyme (ACE) is the key enzyme of the renin angiotensin system (RAS) which maintains the blood pressure homeostasis in our body. The association of the ACE insertion/deletion (I/D) polymorphism with essential hypertension has been demonstrated by many studies. The purpose of the present study is to investigate the association of the insertion/deletion polymorphism of the ACE gene with hypertension and additive diseases in North Indian population. In total, 222 hypertensive and 218 normotensive adults participated in this hospital-based study. Anthropometric measures, lipids profiles, blood glucose, and blood pressure (BP) measures were collected from participants. ACE I/D polymorphism was determined by using insertion-specific amplification. The mean ages of study groups were 50.35 ± 12.40 and 47.32 ± 11.94 for cases and controls, respectively. Significant differences were observed in the frequencies of DD, ID, and II genotypes among the hypertensive and normotensive groups which were found to be 29.7%, 38.7%, and 31.5% vs. 53.7%, 23.4%, and 22.9%, respectively. It has been observed that the ACE ID genotype was significantly (p < 0.05) higher in hypertensive subjects, whereas, the DD genotype was significantly (p < 0.05) higher in control subjects. A strong association was found between cardiovascular diseases (CVDs) and ID genotype [p = 0.017, odds ratio (OR) = 3.091, 95% confidence interval (CI) = 1.224–7.807]. ID [p = 0.002, OR = 2.020, 95% CI = 1.281–3.185] and II [p = 0.032, OR = 1.677, 95% CI = 1.044–2.694] genotypes are more prone to diabetes with hypertension. This finding suggests that ACE insertion/deletion polymorphism is associated with hypertension and additive diseases in North Indians.     

Role of rs1466535 low density lipoprotein receptor-related protein 1 (LRP1) gene polymorphism in carotid artery disease

Objective

An association between rs1466535 low density lipoprotein receptor-related protein 1 (LRP1) gene polymorphism and abdominal aortic aneurysm (AAA) was recently demonstrated. It has not yet been defined if this association is specific for AAA or related to atherosclerosis per se. Therefore, we aimed to evaluate the role of the rs1466535 polymorphism in conferring genetic susceptibility for carotid artery stenosis (CAS).

Methods

The rs1466535 polymorphism was evaluated in n = 814 patients with CAS and n = 814 subjects without evidence of carotid atherosclerosis by TaqMan technology.

Results

The percentage of T allele rs1466535 carriers was significantly higher in CAS patients (49.3%) than in controls (43.9%, p = 0.032). At the multiple logistic regression analysis, the allele T carrier status did not remain a significant determinant of CAS.

Conclusions

The rs1466535 LRP1 polymorphism is not a significant and independent risk factor for CAS. Our result suggests this polymorphism in the LRP1 gene is not associated with atherosclerosis in general as it is not associated with CAS (this study), whereas it is strictly associated with AAA (our previous paper).     

Association of angiotensin II type 1 receptor gene A1166C polymorphism with the presence of diabetes mellitus and metabolic syndrome in patients with documented coronary artery disease

Background

There are relatively limited data available on the genetic susceptibility to diabetes mellitus and metabolic syndrome in the Iranian population. We have therefore investigated the association between the angiotensin II type I receptor gene polymorphism (AT₁R/A1166C) and the presence of diabetes mellitus and metabolic syndrome in a well defined group of patients.

Methods

Patients with angiographically defined coronary artery disease (CAD) (n = 309) were evaluated for the presence of AT₁R/A1166C polymorphism. These patients were classified into subgroups with (n = 164, M/F: 109/55) and without (n = 145, M/F: 84/61) diabetes mellitus. The AT₁R polymorphism was assessed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based method.

Results

There was a higher frequency of polymorphic genotypes (AC + CC) in the diabetic compared with the non-diabetic group (p = 0.01). When determined for each gender separately, this difference remained significant in the males (p = 0.04) but not in females (p = 0.09). With regard to the allele frequencies, the C allele was significantly higher and the A allele frequency was lower in the diabetic group (p = 0.01). This remained significant after gender segregation for males (p = 0.01) but not females. In the binary logistic regression analysis, only serum fasting glucose was found as the independent predictor for the presence of diabetes in the CAD patients (β = 1.16, p < 0.001 for total population and β = 1.29, p < 0.001 for male subjects). There was no significant difference in genotype or allele frequencies between subgroups with and without metabolic syndrome, this being unaffected by gender or the definition of metabolic syndrome used apart from a significantly lower frequency of C allele in male subjects with metabolic syndrome defined by the NCEP ATP III criteria (p = 0.04).

Conclusion

The AT₁R/A1166C polymorphism may be associated with the presence of diabetes mellitus in male subjects with documented CAD.     

Associations of maternal diabetes mellitus and adiponectin gene polymorphisms with congenital heart disease in offspring: A case-control study

This study aimed at assessing the association of maternal diabetes mellitus (DM), the adiponectin gene (APM1) gene polymorphisms, and their interactions with risk of congenital heart disease (CHD) in offspring.A case-control study of 464 mothers of CHD patients and 504 mothers of healthy children was conducted.After adjusting for potential confounding factors, our study suggested that mothers with gestational DM (GDM) during this pregnancy (adjusted odds ratio [aOR = 2.96]), GDM in previous pregnancy experiences (aOR = 3.16), and pregestational DM in the 3 months before this pregnancy (aOR = 4.52) were at a significantly higher risk of CHD in offspring, when compared with those without any diabetes. The polymorphisms of maternal APM1 gene at rs1501299 (T/T vs G/G: aOR = 3.45; T/G vs G/G: aOR = 1.73) and rs2241766 (G/G vs T/T, aOR = 3.36; G/T vs T/T, aOR = 1.93) were significantly associated with risk of CHD in offspring. In addition, significant interactions between maternal DM and the APM1 genetic variants on the development of CHD were found.Our findings indicate that maternal DM, APM1 gene genetic variants, and their interactions are significantly associated with risk of CHD in offspring. However, more studies in different ethnic populations and with a larger sample and prospective design are required to confirm our findings.     

Angiotensin II type 1 receptor A1166C gene polymorphism: Absence of an association with the risk of coronary artery disease and myocardial infarction and of a synergistic effect with angiotensin-converting enzyme gene polymorphism on the risk of these diseases

Aim There is evidence that interaction between angiotensin II type1 receptor A1166C gene polymorphism and angio-tensin I-convertingenzyme Insertion/Deletion gene variation might have an effecton the risk of myocardial infarction. The study was carriedout in a population of 2244 male Caucasians, whose coronaryanatomy was defined by means of coronary angiography. We analysedthe relationship, on the risk of ischaemic heart disease, ofangiotensin II type 1 receptor A1166C gene variation, not onlyto myocardial infarction but also to coronary artery disease,and its potential interaction with angio-tensin I-convertingenzyme Insertion/Deletion gene polymorphism. Methods and Results No association was detected between angiotensin II type 1 receptorA1166C gene polymorphism and coronary artery disease. Similarly,there was no link to myocardial infarction, either in the totalpopulation or in low risk groups. In addition, most importantly,we found no interaction between angiotensin II type 1 receptorA1166C gene variation and angiotensin I-converting Insertion/Deletionpolymorphism, either in connection with the risk of coronaryartery disease or myocardial infarction. Conclusion This angiotensin II type 1 receptor A1166C gene variation isnot associated with any detectable increase in risk of ischaemicheart disease. The findings of the present study do not suggestthat, as regards risk of coronary artery disease and myocardialinfarction, there is interaction between gene polymorphism andangiotensin I-converting enzyme Insertion/Deletion gene variation.TheEuropean Society of Cardiology     

Cholesteryl ester transfer protein genetic polymorphisms, HDL cholesterol, and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis

The cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, −629C/A, Taq1B, and −2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, carotid intimal-medial thickness (IMT), and carotid artery plaque measured by ultrasonography. Carriers of the 451Q and 373P alleles have a significantly higher CETP concentration (22.4% and 19.5%, respectively; p < 0.001) and activity (13.1% and 9.4%, respectively; p < 0.01) and lower HDL-C (5.6% and 6.0%, respectively; p < 0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p = 0.006 and p = 0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p = 0.036). Polymorphism is associated with neither common nor internal carotid IMT. We confirmed that the −629A, Taq1B B2, and −2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p < 0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p < 0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p < 0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.     

A multigenic study on breast cancer risk associated with genetic polymorphisms of ER Alpha, COMT and CYP19 gene in BRCA1/BRCA2 negative Shanghai women with early onset breast cancer or affected relatives

High penetrance genes such as BRCA1 or BRCA2 account for only a small proportion of familial breast cancer in Chinese population. Estrogen has been proposed to participate in the proliferation and carcinogenesis of breast cancer. To investigate the association between genetic polymorphisms in genes encoding estrogen metabolizing, estrogen biosynthesizing enzyme and estrogen receptor and the breast cancer risk in BRCA1/BRCA2 negative Shanghai women, we conducted a case-control study including 114 cases with early-onset breast cancer or affected relatives and 121 healthy controls. The genotypes of estrogen receptor alpha (ERα), aromatase (CYP19), and catechol-O-methyltransferase (COMT) genes were analyzed by direct DNA-sequencing. Compared with H/H genotype of COMT Val158Met, COMT Val158Met L/L genotype was associated with a nonsignificantly elevated risk of breast cancer (OR: 3.72; 95% CI: 0.99–13.96, P = 0.051). There was no statistically significant difference in genotype frequency of the ERα PvuII, ERα XbaI and CYP19 Arg264Cys polymorphism between controls and cases. When stratified by menopausal status, COMT Val158Met L/L (OR: 11.94; 95% CI: 1.48–96.03, P = 0.02) and ERα PvuII P/p genotypes (OR: 2.67; 95% CI: 1.01–7.05, P = 0.048) were associated with a significantly elevated risk of breast cancer in premenopausal women, and there was a association between ERα XbaI x/x genotype and the nonsignificantly increased risk of breast cancer in premenopausal women (OR: 6.88; 95% CI: 0.80–59.15, P = 0.079). The multigenic analysis showed maybe these high risk genotypes had combined effect on breast cancer risk. Our findings suggest that polymorphism of genes involving estrogen-metabolizing pathway, estrogen- biosynthesizing pathway and estrogen receptor pathway may play an important role in the etiology of BRCA1/2 negative breast cancer with hereditary predisposing factors. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Zhen Hu and Chuan-Gui Song contributed equally to the work.     

Gene-air pollution interaction and cardiovascular disease: a review

Genetic susceptibility is likely to play a role in response to air pollution. Hence, gene-environment interaction studies can be a tool for exploring the mechanisms and the importance of the pathway in the association between air pollution and a cardiovascular outcome.In this article, we present a systematic review of the studies that have examined gene-environment interactions in relation to the cardiovascular health effects of air pollutants.We identified 16 articles meeting our search criteria. Of these studies, most have focused on individual functional polymorphisms or individual candidate genes. Moreover, they were all based on 3 study populations that have been extensively investigated in relation to air pollution effects: the Normative Aging Study, Air Pollution and Inflammatory Response in Myocardial Infarction Survivors: Gene-Environment Interaction in a High Risk Group, and Multiethnic Study of Atherosclerosis.In conclusions, the studies differed substantially in both the cardiovascular outcomes examined and the polymorphisms examined, so there is little confirmation of results across cohorts. Gene-environment interaction studies can help explore the mechanisms and the potential pathway in the association between air pollution and a cardiovascular outcome; replication of findings and studies involving multiple cohorts would be needed to draw stronger conclusions.     

Association of TLR3 gene 1377C/T (rs3775290) and TLR7 gene C/G (rs3853839) polymorphism with hand,foot, and mouth disease caused by human enterovirus 71 infection susceptibility and severity in the Chinese Han population: A meta-analysis of case-control studies

Background:Several case-control studies have been conducted on the relationship between rs3775290 C/T and rs3853839 C/G single nucleotide polymorphisms of the Toll-like receptor (TLR) gene and hand, foot, and mouth disease (HFMD) susceptibility and severity. This meta-analysis aimed to offer a systemic review of HFMD susceptibility and severity among the Chinese Han population associated with the C/T (rs3775290) polymorphism of the TLR3 gene or C/G (rs3853839) polymorphism of the TLR7 gene.Methods:A computer search was conducted using PubMed, Web of Science, Embase, CNKI, CBM, VIP, and WanFang databases. The time ranges were from database establishment to 30/7/2021. Articles selected according to the inclusion and exclusion criteria underwent data extraction and methodological quality evaluation. RevMan 5.4 and Stata 16.0 were adopted for meta-analysis, and the incorporated odds ratio (OR) values and 95% confidence intervals (CIs) were calculated. Sensitivity and publication bias assessments were performed.Results:8 articles with 9 studies were selected. Among them, there were 858 cases and 577 controls in TLR3 rs3775290 studies as well as 2151 cases and 1554 controls in TLR7 rs3853839 studies. Regarding rs3775290 of TLR3, susceptibilities of the severe type of T-possessing individuals were larger than those of C-possessing individuals [OR = 1.34, 95%CI (1.10, 1.64), P = .004]. The susceptibility of individuals with the severe TT genotype was 1.61 times that of individuals with the CC genotype [95%CI (1.07, 2.43), P=0.02], while susceptibility to HFMD was not influenced by the genotype. In terms of the rs3853839 of the TLR7 gene, C allele carriers have a higher risk of developing HFMD than G allele carriers. The susceptibility to HFMD in CC+CG individuals was 1.24 times than that in GG individuals [95%CI (1.07, 1.43), P = .004]. However, no relationship was found between this polymorphism and severity of the severe type. No significant publication bias was observed in this study.Conclusions:rs3775290 (C/T) of TLR3 is associated with susceptibility to the severe type, whereas rs3853839 (C/G) of TLR7 is associated with susceptibility to HFMD. However, owing to the limited quantity and quality of the research, the aforementioned conclusions are yet to be justified by more high-quality research.     

The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China.

AIM: High incidence rates of hepatocellular carcinoma (HCC) in Guangxi, China, are primarily due to heavy aflatoxin B1 (AFB1) exposure via corn and groundnut consumption. This study was designed to examine the polymorphisms associated of three carcinogen-metabolizing genes (namely: GSTM1, GSTT1, and HYL1*2) and one DNA-repair gene (namely: XRCC1), and investigate their role as susceptibility markers for HCC. METHODS: We conducted a case-control study including 257 cases of cancer and 649 hospital-based age, sex, ethnicity, and hepatitis B virus infection-matched controls to examine the role of genetic polymorphisms of four genes (GSTM1, GSTT1, HYL1*2, and XRCC1) in the context of HCC risk for the Guangxi population. Genomic DNA isolated from 2ml whole blood was used to genotype GSTM1, GSTT1, HYL1*2, and XRCC1 by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: GSTT1-null genotype was not significantly associated with the risk of HCC, but GSTM1-null genotype [adjusted odds ratio (OR)=2.29, 95% confidence interval (CI)=1.59-3.31], HYL1*2 genotypes with 113 His allele (namely: YH/HH, adjusted OR=2.55, CI=1.78-3.65), and XRCC1 genotypes with 399 Gln allele (namely: AG/GG, adjusted OR=2.47, CI=1.72-3.54) increased the HCC risk. Compared with those individuals who did not express any putative risk genotypes as reference (OR=1), individuals featuring all of the putative risk genotypes [GSTM1-null, HYL1*2-YH/HH, and XRCC1-AG/GG] did experience a significantly greater cancer risk (adjusted OR=10.83, CI=5.44-21.59, P(interaction)<0.01). Additionally, the risk of HCC did appear to differ more significantly among individuals featuring risk genotypes and high-level or long-term AFB1 exposure, whose adjusted ORs (CIs) were 52.44 (17.51-157.08) and 326.93 (38.58-2770.52), respectively. CONCLUSIONS: The results suggest that carcinogen metabolism and DNA-repair pathways may simultaneously modulate the risk of HCC for Guangxi population, and, particularly for these having high-level or long-term AFB1 exposure.     

The reproductive activity in the testis of Podarcis s. sicula involves d-aspartic acid: A study on c-kit receptor protein, tyrosine kinase activity and PCNA protein during annual sexual cycle

The current study provides substantial evidence that the pattern of synthesis of d-aspartic acid (d-Asp) in the testes of lizard Podarcis s. sicula throughout the reproductive cycle is in parallel with seasonal variations of testosterone, c-kit receptor protein, tyrosine kinase activity, and proliferating cell nuclear antigen (PCNA) protein. Although the trend is the same in all phases of the sexual cycle, the peaks of these three molecules are detectable only during the reproductive period. Using Western blot technique, we demonstrated that both polyclonal c-kit and PCNA antibodies specifically recognized bands with molecular mass of ∼150 and ∼36 kDa, respectively. By immunocytochemical methods, d-Asp immunopositivity appeared spread in the germinal epithelium as well as in the interstitial compartment of the testes. We also found specific c-kit labeling in I and II spermatogonia (SPG), in I and II spermatocytes (SPC), in the elongated spermatides, in spermatozoa, in Sertoli and Leydig cells. Like c-kit, PCNA positivity was located in the germinal epithelium pattern. Furthermore, we investigated the relationship between testosterone, c-kit receptor, tyrosine kinases activity and PCNA following treatment with d-Asp. In vivo experiments, entailing a single injection of d-Asp (2.0 μmol/g body weight), demonstrated that this amino acid significantly accumulated in the testes. After 3 h, its uptake was accompanied by an increase in testosterone levels and in the expression and intensity of immunostaining of c-kit receptor protein. Furthermore, at 6 h, exogenous d-Asp affected the phosphorylation of tyrosine kinases, whose activation was positively correlated with the temporal uptake of both d-Asp and testosterone detected in the testes. Thereafter, between 6 and 15 h, the expression of PCNA was induced and an increase in its immunolabeling intensity was observed. Taken all together, these results provide new insights into the testicular activity during the reproductive cycle of Podarcis s. sicula, suggesting that a sequential cascade of a functional relationship between testosterone levels, c-kit receptor protein, tyrosine kinase activity and PCNA could be partly mediated by d-aspartic acid.